ACTIVITIES OF NOVEL ARYLOXYALKYLIMIDAZOLINES ON RAT 5-HT2A AND 5-HT2CRECEPTORS

Using transfected NIH 3T3 mouse fibroblast cell lines expressing the r at 5-HT2A and rat 5-HT2C receptor subtypes, and techniques of 2-[I-125 ](+)-iodolysergic acid diethylamide ([I-125]LSD) binding and serotonin (5-hydroxytryptamine, 5-HT)-stimulated phosphoinositide hydrolysis, w e have characterized a new structural class of 5-HT receptor ligands, the aryloxyalkylimidazolines. These compounds were found to be potent competitors of [I-125]LSD binding at both receptor subtypes (K-i simil ar to 5-200 nM) and to have efficacy ranging from potent competitive a ntagonists (IC50 similar to 25 nM) to moderately potent full agonists (EC(50) similar to 200 nM). Some of these compounds are agonists at bo th receptor subtypes, while others are 5-HT2C receptor agonists with 5 -HT2A receptor antagonist activity. None of the aryloxyalkylimidazolin es reported here have 5-HT2A or 5-HT2C receptor selective antagonist a ctivity. Since these compounds are novel structures, we compared them with a variety of reference 5-HT receptor ligands selected from other chemical classes that have previously been studied at 5-HT2A and 5-HT2 C receptors in native tissues.